J. Org. Chem. 1999, 64, 629-633
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Stereoselective Reductive Rearrangement of r-Hydroxy Epoxides: A New Method for Synthesis of 1,3-Diols1 Yong Qiang Tu,* Liang Dong Sun, and Ping Zhen Wang Department of Chemistry & National Laboratory of Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China Received June 9, 1998
A novel and short synthetic method for the stereoselective synthesis of 1,3-diols has been developed by an unusual reductive rearrangement of a series of R-hydroxy epoxides with aluminum isopropoxide. The reaction process was also investigated with deuterium-labeled aluminum isopropoxide, which revealed a site-specific 1,2-carbon-to-carbon migration and successive stereoselective hydride shift. The main synthetically valuable feature is that up to three contiguous carbon centers, the C-1, C-2, and C-3, were stereoselectively controlled with C-2 being quaternary. This reaction is of particular importance to the synthesis of newly developed powerful asymmetric hydrogenation catalysts containing the chiral ligands of spirocyclic diols. Introduction Since the chiral synthesis of R-hydroxy epoxides was carried out by Sharpless asymmetric epoxidation,2 the subject of their reactions and utilization has attracted the research interests of organic chemists.3,4 Although rearrangements of epoxides promoted by Lewis acid are well-known, few, for example, the TiCl4-induced semipinacol rearrangements of epoxy silyl ether, can control up to two carbon centers.3 The aluminum isopropoxide (AIP) mediated stereoselective rearrangement has seldom been reported.3b Recently, our independent research has brought about the discovery of a novel reductive rearrangement of R-hydroxy epoxides effected by AIP, which completes two transformations in one step, the semipinacol rearrangement3a and the Meerwein-PondorfVerley type reduction,5 and leads to the formation of 1,3diol products. The value of this reaction involves the stereoselective derivation of three carbon centers with one being quaternary. The stereoselective construction of a quaternary center is of particular importance because it is one of the more difficult structure classes to access. One of the practical applications is toward the synthesis of chiral 1,3-diols,6 to be used as ligands especially for catalytic hydrogenation.7 This method is short, simple, and effective for preparing chiral diols, and two ap(1) This work has been registered as a Chinese Patent, 97118857.2, 1997. (2) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974. (3) For Lewis acid-catalyzed rearrangements of epoxides, see: (a) for general review, Rickborn, B. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 3, pp 733-755. (b)Morgans, D. J.; Sharpless K. B. J. Am. Chem. Soc. 1981, 103, 462464. (c) Maruoka, K.; Hasegawa, M.; Yamamoto, H.; Suzuki, K.; Shimazaki, M.; Tsuchihashi, G.-i. J. Am. Chem. Soc. 1986, 108, 38273830. (d) Maruoka, K; Sato, J.; Yamamoto, H. J. Am. Chem. Soc. 1991, 113, 5449-5450. (e) Marson, C. M.; Walker, A. J.; Pickering, J.; Hobson, A. D.; Wrigglesworth, R.; Edge, S. J. J. Org. Chem. 1993, 58, 59445951. (4) For some synthetic applications of epoxides, see: (a) Gorzynski Smith, J. Synthesis 1984, 8, 629-656. (b) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. Tetrahedron 1983, 39, 2323-2367. (c) Rossiter, B. E. In Asymmetric Synthesis; Morrison, J. D.; Ed.; Academic Press: Orlando, FL, 1983; Vol. 5, pp 194-246. (5) Haslam, J. H. U.S. Patent 2719863, 1957. (b) Chem. Abstr. 1956, 50, 4217. (6) Blaser, H.-U. Chem. Rev. 1992, 92, 935-952. (b) Zhu, G.; Cao, P.; Jiang, Q.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 1799-1800.
proaches could bring about the chiral synthesis. One would involve the synthesis of a racemic 1,3-diol and then resolution. Alternatively, the chiral 1,3-diols could be synthesized by this rearrangement directly from chiral hydroxy epoxides (e.g., available by alkylation of a chiral allylic epoxy ketone derived by oxidation of the Sharpless epoxidation products or directly from some natural source). Results and Discussion In consideration of the previously reported work on acyclic systems,3 cyclic substrates, including R-hydroxycyclohexene oxides and several R-hydroxycyclopentene oxides, were chosen for our investigation. Thus, as indicated in Scheme 1, the racemic starting R-hydroxy epoxides (prepared from cycloalkenyl chlorides and appropriate ketones,8 excluding 2a and 3a), when treated with AIP under the standard condition (2 equiv of AIP, refluxing temperature of 2-propanol or THF, 4-8 h), underwent a reductive rearrangement to produce 1,3diols in good yields. All the experimental results are tabulated in Table 1, in which only few examples gave rise to allylic diol products resulting from the typical Lewis acid rearrangement (e.g., entries 1, 2, and 4)9 or the simple nucleophilic addition-opening products (e.g., entries 3 and 11). Of all the Lewis acids examined,10 only AIP proved to be effective for this reductive rearrange(7) For synthesis of chiral spirocyclic diols and their application to asymmetric organic reaction, see: (a) Chan, A. S. C.; Hu, W.; Pai, C.C.; Lau, C.-P.; Jiang, Y.; Mi, A.; Yan, M.; Sun, J.; Lou, R.; Deng, J. J. Am. Chem. Soc. 1997, 119, 9570-9571. (b) Chan, A. S. C.; Lin, C.-C.; Sun, J.; Hu, W.; Li, Z.; Pan, W.; Mi, A.; Jiang, Y.; Huang, T.-M.; Yang, T.-K.; Chen, J.-H.; Wang, Y.; Lee, G.-H. Tetrahedron: Asymmetry 1995, 6, 2953-2959. (c) Bru¨nner, R.; Gerlach, H. Tetrahedron: Asymmetry 1994, 5, 1613-1620. (d) Suemune, H.; Maeda, K.; Kato, K.; Sakai, K. J. Chem. Soc., Perkin Trans. 1 1994, 3441-3447. (e) Nieman, J. A.; Parvez, M.; Keay, B. A. Tetrahedron: Asymmetry 1993, 4, 1973-1976. (f) Carruthers, W.; Orridge, A. J. Chem. Soc., Perkin Trans. 1 1977, 2411-2416. (8) Braude, E. A.; Coles, J. A. J. Chem. Soc. 1950, 2014-2019. (9) Eschinasi, E. H. J. Org. Chem. 1970, 35, 1598-1600. (10) We have examined Ti(O-i-Pr)4, Al(OEt)3, Al(O-t-Bu)3, and Ti(O-i-Pr)4 and found them not to be effective toward this reductive rearrangement. The reaction system can be refluxed for 2 days, using the Lewis acids Al(OEt)3 and Al(O-t-Bu)3, affording only a complicated mixture.
10.1021/jo981097z CCC: $18.00 © 1999 American Chemical Society Published on Web 01/06/1999
630 J. Org. Chem., Vol. 64, No. 2, 1999 Scheme 1.
Reaction of r-Hydroxy Epoxides with AIP
ment. In comparison with those promoted by other Lewis acids, such as TiCl4 and SnCl4,3a,c,e this rearrangement exhibited some similar characteristics. For example, two stereoselective carbon centers, C-2 and C-3, were successfully controlled with the C-2 being quaternary. In addition, epoxides containing aryl and methyl or isopropyl at C-1 (entries 6, 11, and 16) revealed the higher migratory aptitude of aryl than methyl and proton, which was consistent with the typical Pinacol rearrangement. Furthermore, the 1,1-disubstituted hydroxy epoxides were more effective toward this rearrangement than the 1-monosubstituted compounds (entry 11), for in several tested examples of monosubstituted substrates only the 1-R-furyl substrate 11a was effective. Again, the carbonto-carbon migration appeared to be in the anti form related to the broken C2-O bond. For entries 7 and 8, the 1H NMR interpretation of 7b and 8b indicated that an unexpected syn migration had taken place. Although this uncommon stereocontrolling process was unclear, the reverse stereoselectivity for both examples was quite good. It was also found that this carbon-to-carbon migration was highly stereoselective with respect to the steric situation of the epoxy moiety but not to the relative configuration of C-1. For example, substrate 2a with a C4-CH3 and epoxy ring being at different faces of the cyclohexane ring, gave the right 1,3-diol 2b, while 3a with the C4-CH3 and epoxy ring at the same face, formed no corresponding 1,3-diol but a simple neucleophilic addition-opening product 3c. This was probably due to the steric repulsion of the syn C4-Me which prevented AIP from coordination with the epoxy oxygen. It was interesting to note that this reductive rearrangement exhibited some surprising properties. For example, epoxides 7a-9a containing ethyl or isopropyl and aryl at C-1 showed an unusual migration order, i.e., isopropyl and ethyl vs aryls, and also gave rise to high yields of 1,3-diols 7b-9b. It is possible that these uncommon migrations incorporated formation of a carbocation intermediate of C-1, and the conjugated π-system of aryl group R1 would be favorable to it (see Scheme 2). Because other examples mentioned above showed the ordinary migration order, we thought that the migration aptitude of R1 and R2 in our investigation scope was isopropyl and ethyl vs phenyl vs methyl. In addition, the stereochemistry of the secondary C1-OH of the 1,3-diols was found to be independent of that of the R-hydroxy epoxide substrates. For example, 10a and 14a, both containing one diastereoisomer, formed the 1,3-diols 10b and 14b with two C1-diastereoisomers, respectively, while 16a, containing a pair of C1-epimers, gave only one. The latter information would be of synthetic importance,
Tu et al.
because a mixture of certain hydroxy epoxides with a chiral epoxy moiety but epimeric at C-1 could be transformed to an optically active 1,3-diol with three contiguous chiral centers. It is also particularly important that the preparation of spirocyclic 1,3-diols, such as 12b through a cycloenlargement of 12a, was of high yield and stereoselectivity,11 which implied powerful practical utilities of this reaction for the synthesis of chiral spirocyclic diol ligands. To assist with the stereochemistry assignments, we first investigated the 1,3-diol products possessing cyclohexanol moieties (entries 1, 2, 4, 6, 9, 10, 12, and 13), whose 1H NMR for H-3 showed a singlet or a narrow doublet with the coupling constant J < 2 Hz. This fact suggested that the C3-OH attached to the cyclohexane rings would be in the axial direction and the migration group R2 would be in the trans-form related to this hydroxyl, due to the fact that the bulkier C-1-bearing moiety attached to C-2 preferred to be in the equatorial direction. In comparison with a literature result,3e the anti-migration products also exhibited similar 1H NMR singlets for H-3. On the basis of this consideration, we thought this rearrangement, except for entries 7 and 8, could mainly include the anti-form of carbon-to-carbon migration. To assign successively the relative stereochemistry of C-1 and C-2, three 1,3-diols 2b, 10b, and 12b, as examples, were chosen for investigation by first preparing their acetonides (rt, excess acetone/p-TsOH, overnight). It was found that the 1H NMR of both 12b and its acetonide showed very similar doublets of doublets for H-1 at δ 3.56 (J ) 11, 4.4 Hz) and 3.39 (J ) 11, 4.2 Hz) and singlets for H-3 at δ 3.59 and 3.45, respectively. A molecular model examination suggested that the relative configuration for both compounds would be C1-C2 syn and C2-C3 anti (as indicated in Scheme 1). In addition, an investigation of the acetonide mixture (80/20) of 10b with 1H,1H-NOESY technique indicated that the major isomer was of the C1-C2 syn configuration and the minor one was of the C1-C2 anti configuration. Again a further investigation of the acetonide of 2b with the 1H,1HNOESY technique also showed the presence of C1-C2 syn configuration. On the basis of the above results, we presumed that the main stereochemistry for this reaction would be C1-C2 syn and C2-C3 anti. Further aspects of the sterochemistry of this rearrangement are currently under investigation. For further examination of the reaction process and thus support for the stereochemistry assignments above, deuterium AIP (prepared from AlEt3 and 2-propanol-d8, see Experimental Section) were used to conduct this reaction. The R-hydroxy epoxide 12a, when treated with deuterium AIP under the typical conditions, gave the spirocyclic diol 13b, whose NMR and MS analyses suggested that the deuterium was located at C-1. On the basis of this fact and some information described above, a possible reaction mechanism thus was suggested (as showed in Scheme 2), in which aluminum complex 6 coordinated first with epoxy oxygen, facilitating a bond cleavage between this oxygen and the crowded quaternary C-2 and forming C1-carbocation intermediate 7. Then a hydride shift from the methine carbon of the (11) In some examples, a larger scale of experiment (e.g., with >1 g of 12a) gave a little lower stereoslectivity of the C-1 center (ca. 5% of 1-epimer of 12b was formed).
Reductive Rearrangement of R-Hydroxy Epoxides
J. Org. Chem., Vol. 64, No. 2, 1999 631
Table 1. Rearrangement of r-Hydroxy Epoxides with AIPa,b
a The structures of all compounds were determined on the basis of NMR and mass spectroscopy, and ratios were established by 1 H NMR and/or GC-MS analysis. b For some examples with lower total yields (e.g., entries 16, 14, and 5), the byproducts were complicated mixtures with very low polarity on TLC and not identified. c The 91:9 for 11b represents a ratio of C2-C3 anti isomer to the syn.
isopropoxy group to the C1-carbocation center in 7 followed by elimination of an acetone molecule and a final hydrolysis or alcoholization thus led to the formation of 1,3-diols 4 and/or 5. Here two possible pathways exist for the hydride shift, a and b, which bring about two corresponding 1,3-diols, the C1-C2 syn 4 and the C1-C2 anti 5, respectively. The shift in pathway b at the back of the six-membered ring consists of an Al atom interacting with an axial proton above the cyclohexane ring, and that in pathway a does not. Thus the C1-C2 syn product 4 was more abundant than the C1-C2 anti 5. In fact, some examples, such as entries 1, 2, 4, 5, 12, 15, and 16, gave the exclusive C1-C2 syn isomers 4. After all, we thought preliminarily that the stereoselectivity of C-1 for the 1,3-diols was mainly dependent on the migration ability of R2, the contribution of R1 to the stability of
the C1-carbocation, and the steric situiation of hydride shift. The reductive rearrangement reported above is indeed a new approach for stereoselective synthesis of 1,3-diols and demonstrates a versatile and practical asymmetric organic reaction.12 By using asymmetric hydroxy epoxides available by the Sharpless procedure or from natural sources, this method enabled a new and stereocontrolled (12) As with the application scope and limitation of this method, we felt this reductive rearrangement could be generally applied to the substrates with 1,1-substituents varying from alkyl to aromatic groups, but not to the 1-monosubstituted substrate. In addition, the C1-alkyl (especially Me) substituted subtrates in some cases gave a low yield of 1,3-diol products though the stereoselectivity of the C-1 center was good, and C1-aromactic substituted substrates generally gave products with lower selectivity of C-1 though the reaction yield was generally high.
632 J. Org. Chem., Vol. 64, No. 2, 1999 Scheme 2. A Suggested Reaction Process of r-Hydroxy Epoxides with AIP
approach to asymmetric synthesis. Thus, as an example, the chiral hydroxy epoxide 2a, prepared from the natural (R)(+)-Pulegone in three steps (see Experimental Section),9 was converted by this procedure smoothly to the chiral 1,3-diol ([R]20D ) +25°(c 2.35, CHCl3)) with four asymmetric centers, though the yield was merely 25%.
Experimental Section General Method. The 1H NMR, 13C NMR, and DEPT data and 1H,1H-NOESY spectra were obtained in CDCl3 with TMS or CDCl3 as internal standards. GC-MS, MS, and HRMS data were measured with EI (70 eV) or FAB techniques. Column chromatographies were performed generally on silica gel (200300 mesh) eluting with petroleum ether/EtOAc (20:1 f 10:2) and TLC inspections on silica gel F254 plates with petroleum ether/EtOAc (10:2.5) unless otherwise noted. All starting R-hydroxy epoxides, except for 2a and 3a, were prepared by literature procedures8 as in Scheme 1 and characterized by NMR and mass spectroscopy. 2-(1-Hydroxyethyl)-2-methylcyclohexanol (1b) and 2-(1Hydroxy-1-methylethyl)-2-cyclohexen-1-ol (1c). The procedure described is a general method for all reductive rearrangement experiments unless otherwise noted. A mixture of R-hydroxy epoxide 1a (0.5 g, 3.2 mmol), aluminum isopropoxide (1.3 g, 6.4 mmol), and 2-propanol (10 mL) was refluxed with stirring under Ar for 8 h. After TLC examination indicated the disappearance of the starting material, the solvent was removed in vacuo and the obtained gel residue was partitioned with ether and a 10% NaOH solution. The aqueous layer was separated and re-extracted with ether. The combined ether solution was washed with water and brine, dried (Na2SO4), concentrated in vacuo, and chromatographed on silica gel to give a mixture of 1b and 1c (0.31 g). The ratio was determined to be 43:57 on the basis of the 1H NMR data and the yields were about 26% and 36%, respectively. The partially separated samples could be purified by careful chromatography. Compound 1b: 1H NMR δ 0.80 (s, 3H), 1.11 (d, J ) 6.3 Hz, 3H), 1.18-1.82 (m, 8H), 3.67 (s, 1H), 3.81 (q, J ) 6.3 Hz, 1H); 13C NMR δ 17.2, 2 × 19.5, 20.7, 23.6, 30.0, 39.7, 75.7, 76.0; GC-MS m/z (%) 140 (M+ - 18, 5), 125 (6), 96 (100); HRMS 140.1188, cacld for C9H16O 140.1197. Compound 1c: 1H NMR δ 1.38, 1.41 (2 s, 2 × 3H), 1.25-2.13 (m, 6H), 4.49 (t, J ) 4 Hz, 1H), 5.78 (t, J ) 4 Hz, 1H); 13C NMR δ 16.7, 25.2, 29.3, 29.7, 31.4, 64.3, 73.5, 123.6, 143.1; GC-MS m/z (%) 138 (M+ - 8, 20), 123 (47), 82 (26), 43 (100); HRMS 138.1008, calcd for C9H14O 138.1041. (1R,2S,4R)-4-Methyl-1-(1-hydroxy-1-methylethyl)-1,2epoxycyclohexane (2a) and (1S,2R,4R)-4-Methyl-1-(1hydroxy-1-methylethyl)-1,2-epoxycyclohexane (3a). To an ice-water cooling solution of (4R)-1-(1-hydroxy-1-methylethyl)-4-methylcyclohexene (9 g, 58.4 mmol, prepared by a literature procedure9) in CH2Cl2 (200 mL) was added in portions 65% m-CPBA (18.6 g, ca. 70 mmol) with stirring. After completing addition, stirring was continued for 2 h, and TLC
Tu et al. inspection (petroleum ether/EtOAc 10:1) showed the disappearance of starting material. The reaction system was washed with a saturated NaHCO3 solution, dried (Na2SO4), concentrated, and chromatographed to yield a mixture of 2a/3a (7.3 g, 73%) in a ratio of 75:25, determined by GC-MS. Pure 2a was available by HPLC resolution. Compound 2a: 1H NMR δ 0.82 (d, J ) 6.6 Hz, 3H), 1.18 (s, 6H), 1.22-2.16 (m, 7H), 3.34 (s, 1H); 13C NMR δ 21.3, 24.2, 24.5, 25.2, 25.3, 30.0, 33.7, 56.3, 64.8, 69.9; GC-MS m/z (%) 155 (M+ - 5, 4), 112 (13), 97 (34), 70 (100); HRMS 155. 1055, calcd for C9H15O2 155. 1068. Compound 3a: 1H NMR δ 0.84 (d, J ) 6.4 Hz, 3H), 1.16, 1.20 (2 s, 2 × 3H), 1.22-2.16 (m, 7H), 3.29 (d, J ) 5.5 Hz, 1H); 13C NMR δ 21.7, 24.3, 24.5, 26.0, 27.6, 27.9, 32.7, 55.5, 65.1, 69.7; GC-MS m/z (%) 155 (M+ - 15, 4), 97 (28), 84 (13), 71 (13), 70 (100). (1S,2R,5R)-2-(1-Hydroxyethyl)-2,5-dimethylcyclohexanol (2b) and (3S,5R)-2-(1-Hydroxy-1-methylethyl)-5-methylcyclohexen-1-ol (2c). Following the typical procedure (above, 2 equiv of AIP, refluxing temperature, 8 h), the epoxide 2a (2 g, 11.8 mmol) gave a mixture of 2b/2c (1.4 g) in 25% and 45% yields. The partially separated samples could be purified by careful chromatography. Compound 2b: 1H NMR δ 0.37 (s, 3H), 0.85 (d, J ) 6.4 Hz, 3H), 1.08 (d, J ) 6.4 Hz, 3H), 0.96-1.83 (m, 7H), 3.32 (s, OH), 3.66 (s, 1H), 3.79 (q, J ) 6.4 Hz, 1H); 13C NMR δ 17.3, 19.6, 22.2, 23.8, 25.8, 29.6, 38.9, 39.4, 75.7, 76.7; GC-MS m/z (%) 154 (M+ - 18, 2), 139 (154 15, 7), 110 (77), 95 (100), 81 (33); HRMS 139.1105, calcd for C9H15O 139.1119. Compound 2c: 1H NMR δ 0.93 (d, J ) 6.4 Hz, 3H), 1.32, 1.38 (2 s, 6H), 1.45-2.19 (m, 5H), 3.03 (s, OH), 4.45 (d, J ) 1.3 Hz, 1H), 5.73 (dd, J ) 5.4, 2.4 Hz, 1H); 13C NMR δ 21.5, 22.6, 29.7, 30.1, 34.1, 39.6, 64.4, 73.7, 124.3, 142.9; GC-MS m/z (%) 152 (M+ - 18, 7), 137 (22), 109 (14), 95 (18), 43 (100); HRMS 152.1177, calcd for C10H16O 152.1197. (1S,2S,4R)-1-(1-Hydroxy-1-methylethyl)-2-isopropoxy4-methylcyclohexanol (3c). Following the typical procedure (above, 2 equiv of AIP, refluxing temperature, 8 h), the mixture of 3a/2a (3 g, 17.6 mmol, 25/75) gave the products 3c (0.69 g, 69%) and the mixture of 2b/2c (1.4 g) in a ratio of 35:65. Compound 3c: 1H NMR δ 0.85 (d, J ) 6.4 Hz, 3H), 1.14 (d, J ) 6 Hz, 6H), 1.17, 1.28 (2 s, 6H), 1.24-2.14 (m, 7H), 3.76 (m, 1H), 4.01 (s, 1H); 13C NMR δ 21.3, 22.0, 23.8, 24.0, 25.0, 25.1, 26.4, 29.7, 33.0, 67.8, 73.7, 75.3, 76.1; GC-MS m/z (%) 212 (M+ - 18, 1), 171 (M+ - 59, 6), 129 (34), 112 (100), 97 (62); HRMS 171.1375, calcd for C10H19O2 171.1380. 2-Ethyl-2-(1-hydroxyethyl)cyclohexanol (4b) and 2-(1Hydroxy-1-methylpropyl)-2-cyclohexen-1-ol (4c). Following the typical procedure (above, 2 equiv of AIP, refluxing temperature, 8 h), the epoxide 4a (0.74 g, 44 mmol) gave the product of 4b/4c (0.56 g) in a ratio of 57:43. The partially separated samples could be purified by careful chromatography. Major isomer of 4b: 1H NMR δ 0.68 (t, J ) 7.4 Hz, 3H), 1.02 (d, J ) 6.4 Hz, 3H), 0.77-1.85 (m, 10H), 3.91 (s, 1H), 3.95 (q, J ) 6.4 Hz, 1H), 4.29 (s, OH); 13C NMR δ 6.9, 17.0, 19.3, 20.3, 23.1, 25.4, 29.3, 40.6, 2 × 72.9; GC-MS m/z (%) 154 (M+ - 18, 2), 136 (M+ - 36, 6), 110 (88), 82 (23), 81 (100); HRMS 136.1240, calcd for C10H16 136.1248. Minor isomer of 4b: no NMR data could be collected because of its poor resolution with background; GC-MS m/z (%) 154 (M+ - 18, 1), 136 (5), 96 (100), 95 (20), 81 (96). Compound 4c: 1H NMR δ 0.70 (t, J ) 7.4 Hz, 3H), 0.77-2.03 (m, 8H), 1.25 (s, 3H), 4.31 (t, J ) 4 Hz, 1H), 5.65 (t, J ) 4 Hz, 1H), 4.29 (s, OH); 13C NMR δ 9.1, 17.3, 25.4, 26.2, 31.4, 34.5, 64.6, 76.7, 125.7, 141.2; GC-MS m/z (%) 152 (M+ - 18, 7), 141 (30), 123 (100), 81 (15), 79 (19); HRMS 152.1203, calcd for C10H16O 152.1197. 2-(1-Hydroxy-3-methylbutyl)-2-(2-methylpropyl)cyclohexanol (5b). Following the typical procedure (above, 2 equiv of AIP, refluxing temperature, 8 h), the epoxide 5a (0.3 g, 1.2 mmol) gave the product 5b (0.16 g, 53%): 1H NMR δ 0.780.85 (m, 12H), 0.90-1.90 (m, 14H), 4.09-4.16 (m, 2H), 4.34 (s, OH); 13C NMR δ 17.7, 19.6, 20.3, 21.4, 21.9, 24.0, 24.1, 25.0, 25.1, 29.6, 41.6, 42.2, 49.8, 73.2, 73.6; GC-MS m/z (%) 224 (M+ - 18, 4), 123 (39), 97 (39), 96 (100), 84 (45); HRMS 224.2140, calcd for C15H28O 224.2133. 2-(1-Hydroxyethyl)-2-phenylcyclohexanol (6b). Following the typical procedure (above, 2 equiv of AIP, refluxing
Reductive Rearrangement of R-Hydroxy Epoxides temperature, 8 h), the epoxide 6a (1.0 g, 4.6 mmol) gave a mixture of two isomers of 6b (0.85 g, 85%) in a ratio of 80:20. Major isomer: 1H NMR δ 0.70 (d, J ) 6.4 Hz, 3H), 1.25-2.16 (m, 8H), 4.08 (q, J ) 6.4 Hz, 1H), 4.66 (s, 1H), 7.18-7.38 (m, 5H); 13C NMR δ 17.7, 19.1, 19.6, 21.0, 29.6, 48.4, 74.7, 76.3, 126.0-128.3, 141.8; GC-MS m/z (%) 202 (M+ - 18, 5), 158 (100), 143 (30), 130 (33), 129 (33); HRMS 202.1345, calcd for C14H18O 202.1353. Minor isomer: 1H NMR δ 0.87 (d, J ) 6.4 Hz, 3H), 1.25-2.16 (m, 8H), 3.90 (q, J ) 6.4 Hz, 1H), 4.81 (s, 1H), 7.18-7.38 (m, 5H); 13C NMR δ 17.7, 19.6, 21.4, 27.0, 29.2, 49.1, 69.5, 73.9, 126.0-128.3, 141.0; GC-MS m/z (%) 202 (M+ - 18, 6), 158 (100), 143 (28), 130 (30), 129 (28). 2-Ethyl-2-(1-hydroxy-1-phenylmethyl)cyclohexanol (7b). Following the typical procedure (above, 2 equiv of AIP, refluxing temperature, 8 h), the epoxide 7a (0.2 g, 0.86 mmol) gave a mixture of two isomers of 7b (0.19 g, 95%) in a ratio of 72:28. Major isomer: 1H NMR δ 0.68-0.82 (m, 3H), 0.77-2.18 (m, 10H), 3.66 (dd, J ) 8.8, 1.7 Hz, 1H), 4.17(s, OH), 4.56 (s, 1H), 7.09-7.29 (m, 5H); 13C NMR δ 11.0, 10.9, 20.5, 21.0, 23.9, 29.6, 48.5, 74.7, 82.1, 125.8-129.8, 141.8; GC-MS m/z (%) 216 (M+ - 18, 3), 158 (100), 143 (24), 130 (28), 129 (24); HRMS 216.1500, calcd for C15H20O 216.1509. Minor isomer: 1H NMR δ 0.68-0.82 (m, 3 H), 0.77-2.18 (m, 10 H), 3.43 (dd, J ) 9.0, 1.5 Hz, 1 H), 4.17 (s, OH), 4.72 (s, 1H), 7.09-7.29 (m, 5H); 13C NMR δ 11.2,19.9, 21.4, 24.2, 27.0, 29.1, 49.0, 69.6, 80.3, 125.8129.8, 141.4; GC-MS m/z (%) 216 (M+ - 18, 3), 158 (100), 143 (26), 131 (10), 130 (28). 2-Ethyl-2-(1-hydroxy-1-(6-methoxy-2-naphthyl)methyl)cyclohexanol (8b). Following the typical procedure (above, 2 of equiv AIP, refluxing temperature, 8 h), the epoxide 8a (0.4 g, 1.28 mmol) gave a mixture of two isomers of 8b (0.29 g, 73%) in a ratio of 65:35. Major isomer: 1H NMR δ 0.68 (t, J ) 7.3 Hz, 3H), 0.76-2.17 (m, 10H), 3.76 (dd, J ) 10, 2 Hz, 1H), 3.84 (s, 3H), 4.70 (s, 1H), 7.03-7.65 (m, 6H); 13C NMR δ 11.2, 19.3, 21.0, 21.4, 24.3, 29.8, 48.7, 55.4, 74.9, 83.0, 105.3137.2, 157.7; GC-MS m/z (%) (mixture of 2 isomers) 296 (M+ - 18, 3), 249 (3), 239 (19), 238 (100); HRMS 296.1780, calcd for C20H24O2 296.1770. Minor isomer: 1H NMR δ 0.76-2.16 (m, 1H), 3.55 (dd, J ) 10, 2 Hz, 1H), 3.83 (s, 3H), 4.75 (s, 1H), 7.03-7.65 (m, 6H); 13C NMR δ 11.5, 20.2, 21.7, 24.5, 27.3, 29.4, 49.2, 55.4, 70.0, 80.5, 118.7-136.8, 157.7. 2-(1-Hydroxy-1-phenylmethyl)-2-isopropylcyclohexanol (9b). Following the typical procedure (above, 2 equiv of AIP, refluxing temperature, 8 h), the epoxide 9a (0.4 g, 1.6 mmol) gave a mixture of two isomers of 9b (0.38 g, 95%) in a ratio of 73:27. Major isomer: 1H NMR δ 0.72, 0.73 (2 d, J ) 6.5 Hz, 2 × 3H), 1.24-2.26 (m, 9H), 3.51 (s, OH), 3.84 (d, J ) 1 Hz, 1H), 4.63 (s, 1H), 7.21-7.40 (m, 5H); 13C NMR δ 16.0, 18.8, 21.1, 21.2, 23.2, 28.7, 29.5, 49.4, 76.0, 84.4, 126.0-129.5, 141.9; GC-MS m/z (%) 230 (M+ - 18, 4), 158 (100), 145 (14), 143 (26), 130 (28); HRMS 230.1651, calcd for C16H22O 230.1665. Minor isomer: 1H NMR δ 0.38, 0.82 (2 d, J ) 6.5 Hz, 2 × 3H), 1.24-2.26 (m, 9H), 3.51 (s, OH), 3.56 (d, J ) 1 Hz, 1H), 4.87 (s, 1H), 7.21-7.40 (m, 5H); 13C NMR δ 15.8, 19.8, 21.4, 23.8, 27.3, 27.8, 29.0, 49.2, 70.0, 82.9, 126.0-129.5, 141.2; GC-MS m/z (%) 230 (M+ - 18, 3), 158 (100), 143 (25), 130 (26), 91 (22). 2-(1-Hydroxy-1-phenylmethyl)-2-phenylcyclohexanol (10b). Following the typical procedure (above, 2 equiv of AIP, refluxing temperature, 8 h), the epoxide 10a (0.5 g, 1.8 mmol) gave a mixture of two isomers of 10b (0.46 g, 91%) in a ratio of 80:20. 1H NMR δ (2 isomers) 1.19-2.42 (m, 16H), 4.17, 4.74, 4.75, 4.94 (4 s, 4 H), 6.65-7.37 (m, 20 H). Major isomer: 13C NMR δ 18.9, 19.9, 20.7, 29.4, 49.3, 74.0, 82.9, 125.9-128.5 (10CH), 140.0, 140.5; GC-MS m/z (%) 264 (M+ 18, 3), 158 (100), 143 (19), 130 (21), 129 (16); HRMS 264.1518, calcd for C19H20O 264.1509. Minor isomer: 13C NMR δ 19.6, 21.2, 26.7, 28.9, 49.5, 67.0, 81.4, 125.9-128.5, 139.8, 140.4; GC-MS m/z (%) 247 (M+ - 18 - 17, 3), 158 (100), 143 (19), 130 (21), 129 (16). 2-(r-Furyl)-2-(hydroxymethyl)cyclohexanol (11b) and 1-((r-Furyl)hydroxymethyl)-2-isopopoxycyclohexanol (11c). Following the typical procedure (above, 2 equiv of AIP, refluxing temperature, 8 h), the epoxide 11a (0.9 g, 4.6 mmol) gave a mixture of 11b (0.49 g, yielding 54%) in a ratio of 91:9 and 11c (0.36 g, 31%). Major isomer of 11b: 1H NMR δ 0.77-
J. Org. Chem., Vol. 64, No. 2, 1999 633 1.94 (m, 8H), 3.23 (s, OH), 3.64, 3.84 (ABq, J ) 11 Hz, 2 × 1H), 4.18 (dd, J ) 6, 3 Hz, 1H), 6.13 (d, J ) 3 Hz, 1H), 6.26 (dd, J ) 3, 1.8 Hz, 1H), 7.28 (d, J ) 1.8 Hz, 1H); 13C NMR δ 21.2, 21.5, 28.3, 29.9, 45.6, 66.8, 71.9, 106.4, 110.0, 141.0, 157.8; GC-MS m/z (%) 196 (M+, 1), 178 (M+ - 18, 46), 135 (92), 134 (49), 108 (100); HRMS 178.0988, calcd for C11H14O2 178.0990. No NMR data for the minor isomer could be collected due to the low intensity and its poor resolution with background. 11c: 1H NMR δ 1.10 (d, J ) 6 Hz, 6H), 0.96-1.84 (m, 8H), 2.97 (s, OH), 3.46 (dd, J ) 7.5, 4 Hz, 1H), 3.68 (hept, J ) 6 Hz, 1H), 4.74 (s, 1H), 6.26 (m, 2H), 7.30 (dd, J ) 2, 1.8 Hz, 1H); 13C NMR δ 21.2, 21.6, 21.9, 23.3, 27.5, 32.2, 70.0, 70.6, 74.0, 80.8, 108.2, 110.0, 141.7, 153.8; GC-MS m/z (%) 221 (M+ - 15 - 18, 23), 178 (72), 148 (41), 135 (96), 108 (100); HRMS 221.1168, calcd for C13H17O3 221.1173. 1,7-Dihydroxyspiro[5.5]undecane (12b). Following the typical procedure (above, 2 equiv of AIP, refluxing temperature, 4 h), the epoxide 12a (0.5 g, 2.7 mmol) gave as the only product 12b (0.49 g, 98%): 1H NMR δ 0.66-2.10 (m, 16H), 3.56 (dd, J ) 11, 4.4 Hz, 1H), 3.59 (s, 1H), 4.31 (s, OH); 13C NMR δ 18.7, 19.6, 19.9, 20.2, 24.8, 29.0, 29.7, 30.3, 40.4, 78.5, 78.6; MS m/z (%) 166 (M+ - 18, 11), 148 (100), 122 (63), 111 (33), 81 (93); HRMS 166.1344, calcd for C11H18O 166.1353. 1,7-Dihydroxy-1-deuteriospiro[5.5]undecane (13b). To the solution of 1.1 mL of 2-propanol-d8 (ca. 14 mmol) in dry THF (20 mL) was added 1.7 mL of a 2.6 M solution of AlEt3 in THF. The mixture was refluxed under Ar for 1 h to give the deuterium AIP solution (ca. 4.4 mmol) which was used directly in the reaction for 12a (0.4 g, 2.2 mmol) according to the typical procedure (above, refluxing temperature, 4 h) to give the product 13b (0.36 g, 88%): 1H NMR δ 1.11-2.06 (m, 16H), 3.54 (s, 1H), 4.55 (s, OH), 4.86 (s, OH); 13C NMR δ 18.6, 19.5, 19.8, 20.0, 24.7, 28.8, 29.4, 30.2, 40.1, 77.9 (t, CD), 78.4; GC-MS m/z (%) 167 (M+ - 18, 12), 149 (100), 122 (47), 95 (38), 81 (95); FAB-HRMS 186.1583, calcd for [C11H19DO2 + H] 186.1599. 2-Benzyl-2-(1-hydroxyethyl)cyclopentanol (14b). Following the typical procedure (above, 2 equiv of AIP, refluxing temperature, 8 h), the epoxide 14a (0.5 g, 2.3 mmol) gave a mixture of two isomers of 14b (0.28 g, 55%) in ae ratio of 71: 29. Major isomer: 1H NMR δ 1.18 (d, J ) 6.5 Hz, 3H), 1.262.83 (m, 8H), 3.95 (q, J ) 6.5 Hz, 1H), 4.17 (t, J ) 6.7 Hz, 1H), 7.04-7.87 (m, 5H); 13C NMR δ 18.5 (CH3), 21.1, 30.5, 36.3, 43.4, 51.2, 70.1, 79.8, 124.7-138.6 (Ph); GC-MS m/z (%) 202 (M+ - 18, 10), 158 (76), 143 (23), 129 (54), 91 (100); HRMS 202.1345 calcd for C14H18O 202.1353. Minor isomer: 1H NMR δ 1.17-2.83 (m, 11H), 3.92 (q, J ) 6.4 Hz, 1H), 4.04 (t, J ) 6.4 Hz, 1H), 7.04-7.87 (m, 5H); GC-MS m/z (%) 202 (M+ 18, 9), 158 (100), 129 (55), 117 (29), 91 (94). 2-(1-Hydroxy-3-methybutyl)-2-(2-methylpropyl)cyclopentanol (15b). Following the typical procedure (above, 2 equiv of AIP, refluxing temperature, 8 h), the epoxide 14a (0.45 g, 2.0 mmol) gave the product 15a (0.39 g, 85%): 1H NMR δ 0.95 (m, 12H), 1.10-2.10 (m, 12H), 4.05 (m, 2H); 13C NMR δ 21.2, 21.3, 2 × 24.2, 24.4, 24.6, 25.4, 32.6, 37.5, 40.7, 47.6, 50.5, 71.6, 81.3; GC-MS m/z (%) 210 (M+ - 18, 1), 153 (10), 124 (100), 123 (13), 97 (31); HRMS 192.1877, calcd for C14H24 192.1872. 2-(1-Hydroxyethyl)-2-phenylcyclopentanol (16b). Following the typical procedure (above, 2 equiv of AIP, refluxing temperature, 8 h), the epoxide 16a (0.57 g, 2.8 mmol) gave the product 16b (0.24 g, 42%): 1H NMR δ 0.84 (d, J ) 6.6 Hz, 3H), 1.48-2.28 (m, 6H), 4.17 (q, J ) 6.6 Hz, 1H), 4.60 (t, J ) 5.4 Hz, 1H), 7.16-7.42 (m, 5H); 13C NMR δ 19.5, 20.7, 31.8, 32.9, 58.5, 71.6, 80.6, 126.5, 4 × 128.0, 141.4S; MS m/z (%) 206 (M+, 23), 188 (69), 144 (100), 129 (89) 105 (95); HRMS 206.1308, calcd for C13H18O2 206.1302.
Acknowledgment. We are grateful for the financial support of the Education Ministry of China and the National Science Foundation of China. We also greatly thank Ms. Wang Kai Qiu, Ms. Hui Ling Liang, Prof. Li Yang, Dr. Yu Xin Cui, and Mr. Qi Xiu Zhu for their helpful measurements of spectroscopic data. JO981097Z
